title: A dystroglycan mutation associated with limb-girdle muscular dystrophy.
abstract: Dystroglycan, which serves as a major extracellular matrix receptor in muscle and the central nervous system, requires extensive O-glycosylation to function. We identified a dystroglycan missense mutation (Thr192→Met) in a woman with limb-girdle muscular dystrophy and cognitive impairment. A mouse model harboring this mutation recapitulates the immunohistochemical and neuromuscular abnormalities observed in the patient. In vitro and in vivo studies showed that the mutation impairs the receptor function of dystroglycan in skeletal muscle and brain by inhibiting the post-translational modification, mediated by the glycosyltransferase LARGE, of the phosphorylated O-mannosyl glycans on α-dystroglycan that is required for high-affinity binding to laminin.
authors.affiliation: Department of Molecular Physiology and Biophysics, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Hara
authors.forename: Burcu
authors.initials: B
authors.lastname: Balci-Hayta
authors.forename: Takako
authors.initials: T
authors.lastname: Yoshida-Moriguchi
authors.forename: Motoi
authors.initials: M
authors.lastname: Kanagawa
authors.forename: Daniel
authors.initials: D
authors.lastname: Beltrán-Valero de Bernabé
authors.forename: Hülya
authors.initials: H
authors.lastname: Gündeşli
authors.forename: Tobias
authors.initials: T
authors.lastname: Willer
authors.forename: Jakob S
authors.initials: JS
authors.lastname: Satz
authors.forename: Robert W
authors.initials: RW
authors.lastname: Crawford
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Burden
authors.forename: Stefan
authors.initials: S
authors.lastname: Kunz
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.forename: Alessio
authors.initials: A
authors.lastname: Accardi
authors.forename: Beril
authors.initials: B
authors.lastname: Talim
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloğlu
authors.forename: Pervin
authors.initials: P
authors.lastname: Dinçer
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D049030:Dystroglycans / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D049030:Dystroglycans